Transcriptome-wide co-expression analysis identifies LRRC2 as a novel mediator of mitochondrial and cardiac function.

Mitochondrial dysfunction contributes to myriad monogenic and complex pathologies. To understand the underlying mechanisms, it is essential to define the full complement of proteins that modulate mitochondrial function. To identify such proteins, we performed a meta-analysis of publicly available gene expression data. Gene co-expression analysis of a large and heterogeneous compendium of microarray data nominated a sub-population of transcripts that whilst highly correlated with known mitochondrial protein-encoding transcripts (MPETs), are not themselves recognized as generating proteins either localized to the mitochondrion or pertinent to functions therein. To focus the analysis on a medically-important condition with a strong yet incompletely understood mitochondrial component, candidates were cross-referenced with an MPET-enriched module independently generated via genome-wide co-expression network analysis of a human heart failure gene expression dataset. The strongest uncharacterized candidate in the analysis was Leucine Rich Repeat Containing 2 (LRRC2). LRRC2 was found to be localized to the mitochondria in human cells and transcriptionally-regulated by the mitochondrial master regulator Pgc-1α. We report that Lrrc2 transcript abundance correlates with that of ß-MHC, a canonical marker of cardiac hypertrophy in humans and experimentally demonstrated an elevation in Lrrc2 transcript in in vitro and in vivo rodent models of cardiac hypertrophy as well as in patients with dilated cardiomyopathy. RNAi-mediated Lrrc2 knockdown in a rat-derived cardiomyocyte cell line resulted in enhanced expression of canonical hypertrophic biomarkers as well as increased mitochondrial mass in the context of increased Pgc-1α expression. In conclusion, our meta-analysis represents a simple yet powerful springboard for the nomination of putative mitochondrially-pertinent proteins relevant to cardiac function and enabled the identification of LRRC2 as a novel mitochondrially-relevant protein and regulator of the hypertrophic response.

Measurement of rotational deformity: using a smartphone application is more accurate than conventional methods.

BACKGROUND: We assessed the accuracy of three different methods measuring the angle between two fixed Kirschner wires for the potential purpose of determining correction during rotational osteotomy of long bones. METHODS: Thirty-one orthopaedic consultants and registrars were prospectively asked to measure the angle between two fixed Kirschner wires in four saw bones models using three different techniques: visual estimation (VE), osteotomy templates (OT), and a contemporary smartphone (iPhone4; SP) with its gyroscopic function. These three methods were compared with the value obtained by computed tomography (CTV), which we considered the preferred value. RESULTS: For the pooled data for all four bone models, the mean difference of the VE compared with the CTV was 5.4° ± 5.3°; the mean difference of the OT compared with the CTV was 2.9 ± 3.8°; and the mean difference of the SP compared with the CTV was 0.8 ± 0.9°. Using the pooled data, the difference between using each of these methods was highly significant, as demonstrated by the one-way analysis of variance across groups (P ≤ 0.001). In addition, for the pooled data the independent t-test between each pair of the three methods (VE and OT, VE and SP, and OT and SP) also demonstrated these differences were highly significant (P ≤ 0.001) for all three comparisons. In this study, the number of years of orthopaedic experience did not significantly influence the ability of individual test subjects. CONCLUSION: Measurement of a rotational deformity using a SP app was significantly more accurate and consistent than both VE and OT. We believe the currently available SP technology provides orthopaedic surgeons with a significantly better alternative method of determining the magnitude of rotational deformity when performing corrective osteotomies.